Late asthmatic reaction decreased after pretreatment with salbutamol and formoterol, a new long-acting β2-agonist

Late asthmatic reaction decreased after pretreatment with salbutamol and formoterol, a new long-acting P,-agonist Mona Palmqvist, MD,* Barbro Balder, RN, BSc,* Olle Lawhagen, MD, PhD,* Bo Melander,*** Nils Svedmyr, and Lars Wihlander, MSc*** Giiteborg, Sweden

MD, PhD,**

The inhibitory effect of salbutamol and formoterol, a new long-acting &agonist for inhalation, on the late asthmatic reaction (LAK), was studied in 12 patients with allergic asthma. After a single-blind, placebo-treatment control, eguipotent bronchodilating doses of inhaled salbutamol (500 pg) and formoterol(30 pg) were administered 30 minutes before bronchial allergen challenge in a double-blind randomized design. The early asthmatic reaction was completely inhibited by both drugs (p < 0.01) but not by placebo. The LAR was also signijcantly inhibited by both drugs (p < 0.01); formoterol was only slightly, but significantly, more effective than salbutamol (p = 0.04). In contrast to some earlier studies, the present study indicates an inhibitory effect of &agonists on the LAR. (J ALLERGY CLIN IMMUNOL 1992;89:844-9.) Key worak Allergic asthma, bronchial late asthmatic reaction

allergen challenge,

Three types of bronchial obstructive reactions may occur after allergen exposure: an isolated EAR within minutes, an isolated LAR within hours, and a dual response that is comprised of both the early and late components. l-5The prevalence of LAR after EAR varies, according to different studies, between 18% to 84%.6-1o The EAR is completely inhibited by p2-agonists when these are administered before a bronchial allergen challenge.‘, “* ‘* The EAR is also inhibited by sodium cromoglycate,‘, “, I2 but only by corticosteroids after several days of treatment.13 Among the antiasthmatic drugs studied in their effect on the LAR, sodium cromoglycate and inhaled corticosteroids are the most effective, whereas drugs, such as p2-agonists, have been reported to exert no or only little effect.‘, I’* l2 The reason may be a too short duration of action of the P,-agonists used at the present time, a lack of antiallergic (prophylactic) effect, or too low concentration of the drug at the tissue level. With previous negative results, it was of interest to study

From the *Asthma and Allergy Center, **Department of Clinical Pharmacology, Sahlgren’s Hospital, University of Goteborg, and ***Medical Department of Ciba-Geigy, Goteborg, Sweden. Received for publication April 16, 1991. Revised Dec. 6, 1991. Accepted for publication Dec. 6, 1991. Reprint requests: Mona Palmqvist, MD, Asthma and Allergy Center, Sahlgren’s Hospital, 413 45 Giiteborg, Sweden. l/1/35402 844

&agonist,

Abbreviations

early asthmatic reaction,

used

Early asthmatic reaction LAR: Late asthmatic reaction PEFR: Peak expiratory flow rate SPT: Skin prick test DSCG: Disodium cromoglycate EAR:

the effect of a P,-agonist with longer duration of action. Thus, formoterol, a new long-acting P,-agonist for inhalation with a bronchodilating effect lasting at least 10 to 12 hours,14* Is was selected as the study drug and analyzed for the effect of EAR and LAR. MATERIAL

AND METHODS

(Table I)

Twelve adult female patients, mean age, 30; range, 20 to. 52 years, were selected. The inclusion criteria were a history of asthma, a positive SPT, end a positive bronchial allergen challenge to the relevant allergen. The SPT reactions were graded in accordancewith the recommendations of the Nordic Society for Allergy Researchin a plus system with 10 mg/ml of histamine hydrochloride as a reference.16 The allergens used were cat (n = 6), horse (n = 3), dog (n = l), and cow dander (n = l), and birch pollen (n = 1) purchased from the Allergological Laboratories (ALK) in Copenhagen, Denmark. The same individual batch was used. For a positive LAR, the PEFR should have fallen by >15% 4 to 10 hours after challenge at a prestudy titration day. None of the patients had recently been exposed to the

i-ate

VOLUME 89 NUMBER 4

asthmaflc

react,w

845

DESIGN : salbutamol

formoterol

Q

pretrial control

allergen LAR ?

dose

double-blind randomized

single-blind

FIG.

1. Study

spontaneous variation

in PEFR

design

TABLE I Pt

A-L. N. G-B. L. G. w. S. R. c. L. G. B. u. L. M. C. I-B. K. L. w. K. F. I-L. 0.

Age (yr)

20 27 30 24 26 36 22 33 52 24 28 38

Sex

FEV (% pred)

F F F F F F F F F F

113 103 122 9.5 104 81 90 86 92 73

F

101

F

76

PEFR (% pred) 105

93 110 105 89 76 105 80 95 84 98 67

SPT

++++ +++ ++++ ++++ +++ ++ +++ +++++ +++ +++ +++ +++++

RAST (class)

2 2 2 1 1 0 3 4 3 3 2 3

Allergen

cat cat Dog cow Horse Cat Cat Horse Cat Cat Horse Birch

Dose

NXJ

I ml)

Treatment

64 + 125 125 + 250 16,000 + 32.000 1 : 500 wti vol” l.ooo + 2,000 32,000 4,000 + 8,000 125 16.000 4.000 + 8.000 500 + 1 ,000 4,000

Pr. Patient: SQUIml, standardized quality units per milliliter;

D, inhaled DSCG when it was required; S, inhaled salbutamol when tt was required; A, antihistamine orally when it was required; i”. theophylline orally on a regular basis: B, terbutalinc orally
relevant allergens, and none of the patients had had an airway infection within 4 weeks before the challenges. All patients had mild asthma with FEV, >70% of the predicted value, and they only occasionally used inhaled P,-agonists (duration, 4 to 6 hours), DSCG, and oral antihistamines (duration, 12 hours). Two patients, however, were also taking oral bronchodilators, one patient, theophylline (duration, 12 hours), and one patient, theophylline plus a pZagonist (duration, 12 hours). Inhaled &agonists and DSCG were withdrawn at least 6 hours before challenge. Oral p2agonists, antihistamines, and theophyllines were withdrawn at least 12 hours before the challenge. None of the patients used inhaled or oral corticosteroids. The study was approved

by the Ethics Commiltee of the University of Gijtcborg and the National Board of Health and Welfare.

Design

(Fig. 1)

The study included 5 test days in which the main comparison (double-blind randomized) was between formoterol (long-acting) and sal butamol (short-acting). Placebo was administered on the first study day, single blindly, to confirm the adequate allergen dose. The study was completed with a control day to study spontaneous variations in PEFR (without allergen) during the corresponding time of the day. On a special day after the double-blind study, the effect of pretreatment with inhaled adrenaline was studied in the

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et al.

same patients (This study will be presentedseparately[Dah16f C, Palmqvist M, Svedmyr N, et al., In manuscript.]): day 0, titration of the allergen dose producing a positive LAR; day 1, single-blind pretreatment with inhaled placebo 30 minutes before allergen challenge (five puffs via spacer); days 2 and 3, double-blind, randomized, crossoverpretreatment with equipotent bronchodilating dosesI of inhaled salbutamol, 500 pg (five puffs of 100 p,g each), or inhaled formoterol, 30 pg (five puffs of 6 p.g each) 30 minutes before challenge. A spacer (Volumatic, Glaxco Co., Hamburg, Germany) was used to optimize the deposition of the aerosol into the airways: control day, without pretreatment and allergen challenge, the patients recordedPEFR (0 to 10 hours) during the same time period as on the preceeding test days. Bronchial

allergen

challenge

The bronchial allergen challenge was conducted in a standardized method” with a Pari Inhalier Boy (Paul Ritzau Pari Wesk, Stamberg, Germany) nebulizer with an output of 0.8 ml/min (continuous nebulization) and a particle sizeof 0.5 to 5.5 pm. For titrating an allergen dose eliciting a positive LAR, two-fold increasing concentrations of the allergen solution were inhaled by tidal volume breathing for 2 minutes with 15minute intervals between the doses.The FEV, was measured at 5, 10, and 15 minutes. The challenge procedurewas started by ALK diluent (2 ml NaCl) followed by the lowest allergen dose, 32 standardized quality units per milliliter (ALK arbitrary unit). Provocation was stopped when the FEV, had dropped by >20% from postdiluent value. The FEV, was then measured at 20, 30, and 40 minutes and every hour up to 6 hours. The PEFR was measured 20 minutes after the last allergen dose and then every hour up to 10 hours. At this point, the patients were administered 30 mg of prednisolone orally and 0.8 mg of salbutamol by inhalation to stop the asthmatic reaction. The individual fall in PEFR after 4 to 10 hours was between 15% to 33% (mean, 21%) from baseline. On the following day (placebo), the last effective allergen dose was administered to five patients. In the other sevenpatients, the next doubling dose was also administered since the fall in WV, was <20% in the early reaction. On the following 2 study days, theseindividual allergen doses(one or two dose steps) were constant. The changes in PEF’Rand FEV, was calculated from the pretreatment values (30 minutes before challenge). Statistics The randomized, double-blind part of the study was analyzed as a two-period crossover trial according to the method of Hills and Am&age.‘* The Wilcoxon’s rank-sum test was used for the comparison between sequencegroups, and p < 0.05 was adopted as the level of significance. RESULTS Early reaction

(Fig. 2)

The mean maximum change in FEV, within 30 minutes after challenge calculated from the pretreatment

value was - 35.6% (range, -27% to - 59%) after placebo, + 6.2% (+ 22% to - 15%) after salbutamol, and + 3.2% (+ 17% to - 13%) after formoterol. The mean change in PEFR at 20 minutes, calculated from the pretreatment value, was -29.4% (range, - 10% to -61%) after placebo, +7.2% (+28% to -3%) after salbutamol, and +4.9% (+ 17% to - 5%) after formoterol. Compared to pretreatment PEFR values, the mean values at this point were significantly different. The FEV, values were, except after formoterol treatment, also significantly different from pretreatment values. The mean fall in FEV, and PEFR was significantly smaller after the two active drugs compared with these values after placebo treatment (p < 0.01). There was no significant difference between the two drugs. Late reaction

(Fig. 2)

The mean maximum change in PEFR 4 to 10 hours after challenge calculated from the pretreatment value was - 15.7% (range, - 4% to - 36%) for placebo, -7.0%(+2%to -3l%)forsalbutamol,and -2.2% ( + 6% to - 24%) for formoterol. The individual results are presented in Table II. The mean maximum fall after pretreatment with formoterol was not significantly different from the pretreatment value, but after pretreatment with placebo and salbutamol, the corresponding fall in PEFR was significant. The mean maximum fall in PEFX (4 to 10 hours) was significantly smaller after formoterol than after salbutamol treatment (p = 0.04). Control

day (Fig. 2)

On the control day, the mean maximum changes in PEFR was - 1% (range, + 5% to -4%). The intraindividual difference at each time was not significant . DISCUSSION The bronchial allergen challenge test is a clinical model for studying allergic asthma. The EAR, which reaches its maximum within 30 minutes, is believed to be a direct effect of the action of mast cell mediators.” The LAR, recurring after some hours, is believed to be due to an inflammatory reaction induced by the mediators generated in the early reaction.*‘-** The bronchial obstruction during the late phase cannot be fully reversed by P,-agonists, indicating the presence of edema of the bronchial mucosa.23 Several studies have supported the hypothesis of a significant inflammatory component during the LAR, which has made the LAR interesting as a model for the development of chronic asthma.24-26

Late

VOLUME 89 NUMBER 4

/

asthmatic

reactwn

847

----placebo

‘\-----A/

A allergenl FIG. 2. PEFR (mean), formoterol, salbutamol, allergen challenge).

TABLE Ii. Maximal (LAR) on titration Pt No. 1 2 3 4 5 6 7 8 9 10 11 I2

9

2345676

immediate and and placebo,

late phase, respectively,

after

percent change in PEFR from baseline day and after pretreatment with inhaled

allergen challenge and pretreatment and on control day (without medication

Placebo

-23

-20 -4

-2 c2

- 10

-2

-16 -21 -18 -33 -16 -30 -15 -27

-4 -9

-11 -6 -30 -21 -36

-11 -25

with or

4 to 10 hours after allergen challenge placebo, salbutamol, and formoterol

Tiiration - 15 - 15 -18

lohrs

Salbutamd

--_

Formoterof 1-2 i- :!

0 -1 -3

-1 +6 i-5 7

0 -31

-11

0 -24

_.8

-17

-8 -12

0 +4 -7 .l_l_

Pt.

Patient

In this study, the new long-acting &-agonist, formoterol, was compared with the more short-acting salbutamo1.*’ Saibutamol, as well as terbutaline, has been reported to be ineffective against the LAR.“, I2 The present study demonstrated, however, an inhibitory effect on the LAR by both active drugs. Formoterol was somewhat more effective than salbutamol (p = 0.04). The effect by formoterol on the LAR might be explained by its long bronchodilating duration. However, the effect of salbutamol can hardly be explained by its bronchodilating effect that, at the time for the LAR, is negligible. Since the effect by

salbutamol appeared to be significant up to more than 10 hours, it is more likely explained by some anfiallergic or anti-inflammatory mechanism. An inhibition of mediator release has also been demonstrated for &agonists in in vitro and in vivo models.2*‘30 These results are supported by later studies on the effect of inhaled salbutamol:” and salmeteroP* on late-phase reactions. Since the placebo-treatment day was not randomized, the placebo values have not been included in the statistical analysis because of the risk of period effects. However, during the randomized period (days 2 and

848

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et al.

3), there was no indication of a period effect, strongly indicating that the differences between placebo and the two active drugs are relevant. There may be several reasons why this study on p2agonists, in contrast to some earlier studies, demonstrated a positive result: different observation times, different study designs, different statistical methods,” and different doses and modes of administration of the drugs.“, ” In subjects with asthma with a varying degree of bronchial obstruction, the pre- and posttreatment values may differ considerably, especially when bronchodilators are being studied. To be able to compare different studies of LAR, the importance of deciding a uniform baseline value has been demonstrated.33 In the present study, we selected the pretreatment value as the most basal and stable baseline value. An LAR cana be mixed with a spontaneous decrease in the patient’s pulmonary function during the day as a consequence of lack or withdrawal of antiasthmatic medication. For this reason, PEFR was also recorded on a separate control day when patients refrained from using any medication. There were no signs of spontaneous deteriorations during the day. There appears to be a general agreement in the literature that the LAR should reach its maximum 4 to 8 hours after allergen exposure. However, there is no general agreement concerning the beginning and end of the reaction, the type of pulmonary function test to be used, and the degree of changes. To be considered a significant LAR in this study, a fall in PEFR of >15% 4 to 10 hours after challenge was required. The 15% limit is chosen mainly because of practical reasons. In the pretrial, in which 25 patients were tested, most of the tested patients demonstrated a varying degree of change in their PEFR, from 0% to 45% fall in PEFR, demonstrating that there is a sliding scale from no reaction to a strong LAR.34 For a more precise clinical definition, we therefore suggest that an LAR is defined as a bronchial obstruction 4 to 10 hours after allergen exposure that significantly exceeds the patient’s spontaneous change in pulmonary function. REFERENCES 1. Booij-Noord H, Orie NGM, de Vries K. Immediate and late bronchial obstructive reactions to inhalation of house dust and protective effects of disodium cromoglycate and prednisolone. J ALLERGY CLIN IMMIJNOL 1971;48:344-54. 2. Hargreave FE, Dolovich J, Robertson DG, Kerigan AT. The late asthmatic responses. Can Med Assoc J 1974;110:415-21. 3. Pepys J. Clinical and therapeutical significance of patterns of allergic reactions of the lungs to extrinsic agents. Am Rev Respir Dis 1977;116:573-88. 4. Herxheimer H. The late bronchial reaction in induced asthma. Int Arch Allergy Appl Immunol 1952;3:323.

CLIN.IMMUNOL. APRIL 1992

Campagne JG van, Knol K, de Vries K. House dust 5. Lookeren provocation in children. Stand J Respir Dis 1969;50:76. 6. Metzger WJ, Nugent K, Richerson HB. Site of airflow obstruction during early and late phase asthmatic responses to allergen bronchoprovocation. Chest 1986;88:369-75. 7. Booij-Noord H, de Vries K, Sluiter HJ, Orie GM. Late bronchial obstructive reaction to experimental inhalation of house dust extract. Clin Allergy 1972;2:43-61. 8. Lam S, Tan F, Chan H, Chan-Yeung M. Relationships between types of asthmatic reaction, nonspecific bronchial reactivity, and specific IgE antibodies in patients with red cedar asthma. J ALLERGY CLIN IMMUNOL 1983;72:134-9. 9. Warner JO, Soothill JF, Price JF, Hey EN. Controlled trial of hyposensitization to Dermafophagoides preronyssinus in children with asthma. Lancet 1978;2:912-5. 10. Robertson DC, Kerigan AT, Hargreave FE, Chalmers R, Dolovich J. Late asthmatic responses induced by ragweed-pollen allergen. J ALLERGY CLIN IMMUNOL 1974;54:244-54. 11. Cockcroft DW, Murdock KY. Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine. J ALLERGY CLIN IMMUNOL 1987;79:734-40. l? Hegardt B, Pauwels R, van der Straeten M. Inhibitory effect of KWD 2131, terbutaline, and DSCG on the immediate and late allergen-induced bronchoconstriction. Allergy 1981; 36: 115-22. 13. Dahl R, Johansson S-A. Importance of duration of treatment with inhaled budesonide on the immediate and late bronchial reaction. Eur J Respir Dis 1982;122(suppl):167-75. 14. Liifdahl CG, Svedmyr N. Formoterol fumarate, a new p2adrenoceptor agonist: acute studies of selectivity and duration of effect after inhaled and oral administration. Allergy 1989;44:264-71. 15. Arvidsson P, Larsson S, L(ifdah1 CG, Melander B, Svedmyr N. Formoterol, a new long-acting bronchodilator for inhalation. Eur Respir J 1989;2:325-30. 16. XI Northern Congress of Allergology. Allergy diagnostics and allergen extracts. Northern standardization. Report II [Symposium]. Acta Allergol 1974;29:222-40. 17. Balder B, LGwhagen 0. Bronkiell allergenprovokation med registrering av snabb och semeaktion. Metodbeskrivning. Draco pro Medico 1989;l: 19-22. 18. Hills M, Armitage P. The two-period crossover clinical trial. Br J Clin Pharmacol 1979;8:7-20. 19. Holgate ST, Benyon RC, Howarth PH, et al. Relationship between mediator release from human lung mast cells in vitro and in vivo. Int Arch Allergy Appl Immunol 1985;77:47-56. 20. Nagy L, Lee TH, Kay AB. Neutrophil chemotactic activity in antigen-induced late asthmatic reaction. N Engl J Med 1982;306:497-501, 21. Durham SR, Lee TH, Cromwell 0, et al. Immunologic studies in allergen-induced late-phase asthmatic reactions. J ALLERGY CLIN IMMUNOL 1984;74:49-60. 22. Durham SR, Kay AB. Eosinophils, bronchial hyperreactivity and late-phase asthmatic reactions. Clin Allergy 1985;15: 411-8. 23. Pepys J, Chan M, Hargreave FE, McCarthy DS. Inhibitory effects of disodium cromoglycate on allergen inhalation tests. Lancet 1968;2:134-7. 24. Metzger WJ, Richerson HB, Worden BS, Monick M, Hunninghake GW. Bronchoalveolar lavage of allergic asthmatic patients following allergen provocation. Chest 1986;89:47783. 25. de Monchy JGR, Kauffman HF, Venge P, et al. Bronchoalse.

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Howarth PH, Durham SR, Lee TH, Kay AH. Church MK. Holgate ST. Influence of albuterol, cromofyn sodium, and upratropium bromide on the airway and circulating mediator rcsponses to allergen responses to allergen bronchial provtwatlor? in asthma. Am Rev Respir Dis 1985;132:986-92. Twentyman OP, Finnerty JP. Holgate ST. Salbutamol Inh:bttv allergen-induced late asthmatic reaction and incrcabe II) ‘2. sponsiveness. Clin Exp Allergy 1990;2O(suppi 1 I:Y~. Twentyman OP, Finnerty JP, Harris A, Palmer J, Hdgatc ST Protection against allergen-induced asthma by ~imrrt~rc~l Lxcet 1990;336: 1338-42. Senn SJ. The use of baselines in clinical hiafs ot bionchodi-lators. Stat Med 1989;8:1339-50. Liiwhagen 0, Aromson B, Balder B, Palmqvist hl. Plaschke P. Hur vanliga och s;abila gr allergiska senreaktioncr’? Svrnska LLkareslllskapets ‘Handlingar [Abstract 1. Nvrie:~ IYOO. I(supp1 1):85.

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